Acid-base equilibrium in living organisms is an important parameter that requires tight regulation. Disruption of pH homeostasis has been implicated in various pathological processes such as ischemia, cystic fibrosis and cancer. Non-invasive real-time pH monitoring of intact living objects is a valuable tool for biomedical applications. As the smallest ion, the mobile proton typically undergoes rapid exchange in acid-base reactions. Therefore the majority of the existing NMR pH detection methods utilize molecular probes exhibiting a pH-dependent chemical shift, which reflects the change of distribution between different protonated states undergoing fast exchange at the NMR time scale. However, the accuracy of these probes can be affected by temperature, ionic strength, local magnetic fields, etc., as those factors may influence the NMR chemical shift in a pH-independent manner. Slowing down proton exchange allows ratiometric pH measurement, which eliminates errors from pH-independent factors. Here, a novel pH sensing strategy based on slow proton exchange is presented. By trapping protons inside a molecule with intramolecular hydrogen bonds the proton exchange rate can be significantly reduced and pH can be measured by using the ratio of the NMR signals from the different protonation states of the pH sensor. This ratiometric strategy is more accurate and selective than the existing methods. Detection of pH in vitro and in living biological systems was successfully demonstrated by using this new approach. 1H-NMR pH titration of pH sensor.

Ratiometric NMR pH sensing based on slow proton exchange

247th National Meeting (2014)

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